Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
  • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
  • C07D493/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
  • A61P25/32—Alcohol-abuse
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents

Definitions

• Major depression is a serious health problem affecting more than 5% of the population, with a life-time prevalence of 15-20%.
• Selective serotonin reuptake inhibitors have produced significant success in treating depression and related illnesses and have become among the most prescribed drugs. They nonetheless have a slow onset of action, often taking several weeks to produce their full therapeutic effect. Furthermore, they are effective in fewer than two-thirds of patients.
• Serotonin selective reuptake inhibitors are well known for the treatment of depression and other conditions. SSRIs work by blocking the neuronal reuptake of serotonin, thereby increasing the concentration of serotonin in the synaptic space, and thus increasing the activation of postsynaptic serotonin receptors.
• a 5HT 1A antagonist would limit the negative feedback and should improve the efficacy of the serotonin reuptake mechanism. (Perez, V., et al., The Lancet, 349:1594-1597 (1997)). Such a combination therapy would be expected to speed up the effect of the serotonin reuptake inhibitor.
• R 1 , R 3 , R 4 , R 5 and R 7 are, independently, hydrogen, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms;
• Y is C ⁇ O or C(R 2 ) 2 and Z is CH 2 , CH 2 CH 2 , CH ⁇ CH or NR 2 , or Y and Z, taken together, form CR 2 ⁇ CH, N ⁇ CR 2 or CR 2 ⁇ N;
• R 2 and R 6 are hydrogen or alkyl of 1 to 6 carbon atoms
• X is CR 7 or N
• a dotted line represents an optional double bond
• n is an integer 0, 1 or 2;
• R 1 is hydrogen, hydroxy, halogen, cyano, trifluoromethyl, alkyl of one to six carbon atoms or alkoxy of one to six carbon atoms. In still more preferred embodiments of the present invention R 1 is hydrogen, halo or methoxy.
• R 2 is hydrogen or lower alkyl. Still more preferred are compounds of Formula I wherein R 2 is hydrogen.
• R 3 , R 4 and R 5 is are independently selected from hydrogen, hydroxy, halo, cyano, carboxamido, alkyl of one to six carbon atoms, or alkoxy of one to six carbon atoms in some preferred embodiments of the present invention.
• R 3 , R 4 and R 5 are still more preferably selected from hydrogen, halogen or cyano.
• R 6 is preferably hydrogen or lower alkyl. R 6 is still more preferably hydrogen.
• Y is preferably C(R 2 ) 2
• Z is preferably CH 2 , CH 2 CH 2 or CH ⁇ CH or in other preferred embodiments Y and Z, taken together, form CR 2 ⁇ CH.
• X is preferably CR 7 .
• R 7 is preferably hydrogen, hydroxy, halo, cyano, carboxamido, alkyl of one to six carbon atoms, or alkoxy of one to six carbon atoms. Still more preferably R 7 is hydrogen, halogen or cyano.
• Still more preferred embodiments of the present invention are those in which R 1 is hydrogen, hydroxy, halo, cyano, trifluoromethyl, alkyl of one to six carbon atoms or alkoxy of one to six carbon atoms; Y is C ⁇ O or C(R 2 ) 2 and Z is CH 2 , CH 2 CH 2 or CH ⁇ CH or Y and Z, taken together, form CR 2 ⁇ CH; R 2 is hydrogen, or lower alkyl; R 3 , R 4 and R 5 are independently selected from hydrogen, hydroxy, halo, cyano, carboxamido, alkyl of one to six carbon atoms, or alkoxy of one to six carbon atoms; n is an integer 0 or 1; and R 6 and the dotted line are defined as above.
• R 1 is hydrogen, halo or methoxy
• Y is C(R 2 ) 2 and Z is CH 2 , CH 2 CH 2 or CH ⁇ CH or Y and Z, taken together, form CR 2 ⁇ CH
• R 2 is hydrogen
• R 3 , R 4 and R 5 are independently selected from is hydrogen, halo or cyano
• R 6 is hydrogen
• n is 0 and the dotted line in the azaheterocycle represents a double bond.
• This invention relates to both the R and S stereoisomers of the aminomethyloxaheterocycle-fused-[1,4]-benzodioxan, as well as to mixtures of the R and S stereoisomers.
• the name of the product of this invention where the absolute configuration of the aminomethyl-oxaheterocycle-fused-[1,4]-benzodioxan is not indicated, is intended to embrace the individual R and S enantiomers as well as mixtures of the two.
• the S stereoisomer is preferred.
• an enantiomer substantially free of the corresponding enantiomer refers to a compound which is isolated or separated via separation techniques or prepared free of the corresponding enantiomer.
• substantially free as used herein means that the compound is made up of a significantly greater proportion of one stereoisomer. In preferred embodiments the compound is made up of at least about 90% by weight of a preferred stereoisomer. In other embodiments of the invention, the compound is made up of at least about 99% by weight of a preferred stereoisomer.
• Preferred stereoisomers may be isolated from racemic mixtures by any method known to those skilled in the art, including high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by methods described herein.
• HPLC high performance liquid chromatography
• Jacques, et al. Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, New York, 1962); Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972).
• Alkyl as used herein refers to an aliphatic hydrocarbon chain and includes straight and branched chains such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, and isohexyl.
• Lower alkyl refers to alkyl having 1 to 3 carbon atoms.
• Alkanamido refers to the group R—C( ⁇ O)—NH— where R is an alkyl group of 1 to 5 carbon atoms.
• Alkanoyloxy refers to the group R—C( ⁇ O)—O— where R is an alkyl group of 1 to 5 carbon atoms.
• Alkanesulfonamido refers to the group R—S(O) 2 —NH— where R is an alkyl group of 1 to 6 carbon atoms.
• Alkoxy as used herein refers to the group R—O— where R is an alkyl group of 1 to 6 carbon atoms.
• Carboxamido as used herein refers to the group —CO—NH 2 .
• Carboalkoxy as used herein refers to the group R—O—C( ⁇ O)— where R is an alkyl group of 1 to 5 carbon atoms.
• Halogen refers to chlorine, bromine, fluorine and iodine.
• Pharmaceutically acceptable salts are those derived from such organic and inorganic acids as: acetic, lactic, citric, cinnamic, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, oxalic, propionic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, glycolic, pyruvic, methanesulfonic, ethanesulfonic, toluenesulfonic, salicylic, benzoic, and similarly known acceptable acids.
• the 2-azaheterocyclylmethyl-furo[3,2-f][1,4]benzodioxans of this invention are prepared as illustrated below. Unless otherwise noted, the variables are as defined above. Specifically, the appropriately substituted 4-benzyloxysalicylaldehyde is alkylated with allyl bromide or chloride in the presence of a suitable base such as sodium hydride or potassium carbonate. The aldehyde moiety is then converted to a phenol via oxidation with meta-chloroperoxybenzoic acid (Baeyer-Villiger reaction), followed by cleavage of the resulting formate ester with methanol over basic alumina.
• a suitable base such as sodium hydride or potassium carbonate
• the phenol thus obtained is then elaborated via alkylation with a glycidyl halide or tosylate in the presence of a base such as sodium hydride or potassium carbonate and the product submitted to a Claisen rearrangement in a refluxing high-boiling solvent such as mesitylene. Cyclization of the Claisen rearrangement product to the benzodioxan is effected via treatment with methanol and sodium bicarbonate.
• cyclization to the dihydrofuran is effected via a Mitsonobu reaction with triphenylphosphine and diethyl or diisopropylazodicarboxylate.
• the fused pyrans of this invention are prepared as illustrated below.
• the 7-benzyloxy-8-allyl benzodioxan-2-methyltosylate described above is treated with borane in tetrahydrofuran, followed by oxidation with hydrogen peroxide to yield the 3-hydroxypropyl derivative.
• Unsaturated pyrans (chromenes) are prepared by the method outlined below. Specifically, the appropriately substituted 7-hydroxybenzodioxan-2-methyltosylate is alkylated with a suitable disubstituted propargyl halide (for example, 3-chloro-3-methyl-1-butyne) under the influence of a base such as potassium carbonate or with a disubstituted propargyl alcohol under the Mitsonobu conditions. The resulting ether is rearranged by refluxing in a high boiling solvent such as diethylaniline to give the chromene directly as a mixture of positional isomers. Separation of the regioisomers by column chromatography and replacement of the tosylate with the appropriate azaheterocycles gives the title compounds of the invention.
• a suitable disubstituted propargyl halide for example, 3-chloro-3-methyl-1-butyne
• a base such as potassium carbonate
• the compounds of the invention in which the fused heterocycle is isoxazole are prepared as illustrated below.
• the 7-benzyloxy-8-allylbenzodioxan-2-methyltosylate described above is treated with bis(acetonitrile) palladium (II) chloride in refluxing methylene chloride or benzene in order to effect an isomerization of the double bond into conjugation with the aromatic ring.
• Cleavage of the olefin with osmium tetroxide and sodium periodate then gives the o-benzyloxybenzaldehyde, which is deprotected as above by treatment with hydrogen over palladium on carbon.
• Cyclization to the isoxazole is effected by treatment with hydroxylamine-O-sulfonic acid and sodium bicarbonate.
• the aldehyde may be treated with the appropriate Grignard reagent and the resulting secondary alcohol oxidized to a ketone with a suitable oxidant such as pyridinium chlorochromate or the Swern reagent.
• a suitable oxidant such as pyridinium chlorochromate or the Swern reagent.
• Deprotection as above and cyclization with hydroxylamine-O-sulfonic acid gives the alkyl substituted isoxazole.
• replacement of the tosylate with azaheterocycles appropriate to the invention gives the title compounds of the invention.
• the compounds of the invention in which the fused heterocycle is oxazole are prepared as illustrated below.
• the o-benzyloxybenzaldehyde described above is treated with a suitable oxidant such as the Jones' reagent (CrO 3 /H 2 SO 4 ) to give the corresponding carboxylic acid.
• a suitable oxidant such as the Jones' reagent (CrO 3 /H 2 SO 4 )
• CrO 3 /H 2 SO 4 Jones' reagent
• Treatment of the acid with diphenylphosphoryl azide and a tertiary base such as diisopropylethylamine in t-butanol effects a Curtius reaction and gives the corresponding aniline protected as the t-butoxycarbonyl (t-BOC) derivative.
• the t-BOC group is removed in an acid such as trifluoroacetic acid and cyclization to the oxazole is effected by refluxing in the appropriate ortho ester.
• an acid such as trifluoroacetic acid
• cyclization to the oxazole is effected by refluxing in the appropriate ortho ester.
• the salicylaldehydes, benzodioxans and azaheterocycles appropriate to the above chemistry are known compounds or can be prepared by one schooled in the art.
• the compounds of the invention may be resolved into their enantiomers by conventional methods or, preferably, the individual enantiomers may be prepared directly by substitution of (2R)-( ⁇ )-glycidyl 3-nitrobenzenesulfonate or tosylate (for the S benzodioxan methanamine) or (2S)-(+)-glycidyl 3-nitrobenzenesulfonate or tosylate (for the R enantiomer) in place of epihalohydrin or racemic glycidyl tosylate in the procedures above.
• the compounds of this invention have the ability to block the reuptake of the brain neurotransmitter serotonin. They are thus useful for the treatment of depression and other diseases commonly treated by the administration of serotonin selective reuptake inhibitor (SSRI) antidepressants, such as obsessive compulsive disorder, panic attacks, generalized anxiety disorder, social anxiety disorder, sexual dysfunction, eating disorders, obesity, addictive disorders caused by ethanol or cocaine abuse and related illnesses.
• SSRI serotonin selective reuptake inhibitor
• the compounds of this invention have affinity for and antagonist activity at brain 5-HT 1A serotonin receptors.
• Antagonist activity at 5-HT 1A receptors was established by using a 35 S-GTP ⁇ S binding assay similar to that used by Lazareno and Birdsall (Br. J. Pharmacol. 109: 1120, 1993), in which the test compound's ability to affect the binding of 35 S-GTP ⁇ S to membranes containing cloned human 5-HT 1A receptors was determined. Agonists produce an increase in binding whereas antagonists produce no increase but rather reverse the effects of the standard agonist 8-OHDPAT. The test compound's maximum inhibitory effect is represented as the I max , while its potency is defined by the IC 50 .
• the compounds of the present invention are combined serotonin reuptake inhibitors/5-HT 1A antagonists and are useful for the treatment of diseases commonly treated by the administration of serotonin selective reuptake inhibitor (SSRI) antidepressants, such as depression (including but not limited to major depressive disorder, childhood depression and dysthymia), anxiety, panic disorder, post-traumatic stress disorder, premenstrual dysphoric disorder (also known as pre-menstrual syndrome), attention deficit disorder (with and without hyperactivity), obsessive compulsive disorder (including trichotillomania), social anxiety disorder, generalized anxiety disorder, obesity, eating disorders such as anorexia nervosa, bulimia nervosa, vasomotor flushing, cocaine and alcohol addiction, sexual dysfunction (including premature ejaculation), and related illnesses.
• SSRI serotonin selective reuptake inhibitor
• the present invention provides methods of treating, preventing, inhibiting or alleviating each of the maladies listed above in a mammal, preferably in a human, the methods comprising providing a pharmaceutically effective amount of a compound of this invention to the mammal in need thereof.
• compositions for treating or controlling disease states or conditions of the central nervous system comprising at least one compound of Formula I, mixtures thereof, and or pharmaceutical salts thereof, and a pharmaceutically acceptable carrier therefore.
• Such compositions are prepared in accordance with acceptable pharmaceutical procedures, such as described in Remingtons Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, Pa. (1985).
• Pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and biologically acceptable.
• the compounds of this invention may be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers.
• Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or an encapsulating material.
• the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
• the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
• the powders and tablets preferably contain up to 99% of the active ingredient.
• Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
• Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs.
• the active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat.
• the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
• suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above e.g.
• cellulose derivatives preferably sodium carboxymethyl cellulose solution
• alcohols including monohydric alcohols and polyhydric alcohols e.g. glycols
• oils e.g. fractionated coconut oil and arachis oil
• the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
• Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
• Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.
• the pharmaceutical composition is in unit dosage form, e.g. as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories.
• the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
• the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.
• the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
• the amount provided to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, and the state of the patient, the manner of administration, and the like.
• compounds of the present invention are provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications.
• An amount adequate to accomplish this is defined as a “therapeutically effective amount.”
• the dosage to be used in the treatment of a specific case must be subjectively determined by the attending physician.
• the variables involved include the specific condition and the size, age and response pattern of the patient.
• a starting dose is about 5 mg per day with gradual increase in the daily dose to about 150 mg per day, to provide the desired dosage level in the human.
• Provide as used herein means either directly administering a compound or composition of the present invention, or administering a prodrug, derivative or analog which will form an equivalent amount of the active compound or substance within the body.
• the present invention includes prodrugs of compounds of Formula I.
• “Prodrug”, as used herein means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of Formula I.
• Various forms of prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed).

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• 2002
  • 2002-04-24 EP EP02728947A patent/EP1381613B1/en not_active Expired - Lifetime
  • 2002-04-24 US US10/131,340 patent/US6552049B2/en not_active Expired - Fee Related
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  • 2002-04-24 AT AT02728947T patent/ATE279415T1/de not_active IP Right Cessation
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  • 2002-04-24 WO PCT/US2002/012831 patent/WO2002088135A1/en active IP Right Grant
  • 2002-04-24 ES ES02728947T patent/ES2229138T3/es not_active Expired - Lifetime
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